ort term goals include trying to infer more useful microstructural information from our MRI signal, such as mean cell volume, extracellular volume, intracellular volume, and membrane permeability within a region of tissue as large as 1mm x 1mm x 1mm (using conventional MRI), and as small as 15 micron x 15 micron x 15 micron (using microscopic MRI). With Yoram Cohen, Professor of Chemistry at Tel Aviv University, we are applying DT-MRI to isolated optic nerve bundles, so that we can improve our ability to view or identify structural features in these different compartments. A recent Israel/US Bi-National Science Foundation Grant that we applied for, and received in '98, should help support this activity. Kimberlee Potter, who will be working with us full-time in January 1999, will be studying extracellular matrices, such as neocartilage tissue cultures. She will investigate the relationship between the NMR signal and tissue structure, with the hope that by using the NMR signal, we will be able to follow microstructural changes in cartilage in vivo, as we have done successfully in the brain. When Ferenc Horkay arrives in '99, he will work on developing anisotropic diffusion phantoms made of polymeric gels, whose properties and structure we can control and measure using other experimental techniques (e.g., x-ray diffraction, neutron scattering, ?). This again will allow us to calibrate our MRI diffusion measurements, and other performing our techniques in other Centers. More importantly, these phantom studies will help us develop a better understanding of the relationship between ultra and microstructure and the NMR signal that we measure. A collaboration with Akram Aldroubi at Vanderbilt University is resulting in a mathematical framework for analyzing and representing these complex diffusion tensor data sets, which are inherently discrete, noisy, and voxel-averaged. This work is providing continuous, smoothed tensor fields, with subvoxel resolution. This development will allow us to apply all of the machinery of differential geometry to study our measured tensor fields. The main utility of this will help us follow fiber tracts as well as introduce several new MRI "stains" that reveal architectural features of tissues, such as its local curvature. Work with Sini Pajevic (CIT) is resulting in a statistical framework of tensor imaging which will permit us to answer important question using the powerful methods of hypothesis testing, which will aid us in quantitatively addressing issues such as whether nerve or muscle fiber tracts are continuos, or whether different regions of the brain are connected to each other via fiber tract pathways. Finally, with Carlo Pierpaoli, will we continue our in vivo animal studies, which employ DT-MRI to follow cortical development in kittens. Clinical studies in infants may be possible under a recent NINDS/NIMH joint RPF for pediatric neuroimaging which identifies the intramural NIH program as a possible site for clinical diffusion tensor MRI studies."